U.S. patent number 6,344,050 [Application Number 09/218,336] was granted by the patent office on 2002-02-05 for use of pegylated photosensitizer conjugated with an antibody for treating abnormal tissue.
This patent grant is currently assigned to Light Sciences Corporation. Invention is credited to James C. Chen.
United States Patent |
6,344,050 |
Chen |
February 5, 2002 |
Use of pegylated photosensitizer conjugated with an antibody for
treating abnormal tissue
Abstract
A photosensitizer suitable for use in administering photodynamic
therapy (PDT), conjugated with antibodies that are targeted to
antigens on abnormal tissue and polyethylene glycol (PEG) or other
polymer that extends the residence time of the conjugate within a
patient's body. The resulting pegylated targeted conjugate is
administered to a patient, and after the antibodies have had
sufficient time to bind with the antigens, light from an external
or internal source having a waveband corresponding to an absorption
waveband of the photosensitizer is administered. Use of an external
light source that emits relatively long wavelength light enables
the light to pass through any intervening dermal layer and normal
tissue between the external light source and the treatment site.
Since the photosensitizer in the conjugate is bound to the abnormal
tissue, the light therapy has minimal effect on the intervening
normal tissue. Furthermore, the efficacy of the PDT is enhanced due
to the increased concentration of the photosensitizer of the
conjugate linked to the abnormal tissue.
Inventors: |
Chen; James C. (Bellevue,
WA) |
Assignee: |
Light Sciences Corporation
(Issaquah, WA)
|
Family
ID: |
22814698 |
Appl.
No.: |
09/218,336 |
Filed: |
December 21, 1998 |
Current U.S.
Class: |
607/88; 128/898;
606/14; 606/2 |
Current CPC
Class: |
A61K
41/0057 (20130101); A61K 47/6927 (20170801); A61K
47/68 (20170801); A61K 47/60 (20170801) |
Current International
Class: |
A61K
41/00 (20060101); A61K 47/48 (20060101); A61N
007/00 () |
Field of
Search: |
;606/2,3,7,10,11,12,14,15 ;424/78.08,78.17 ;128/898
;530/390.1,391.7 ;607/58 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 91/10743 |
|
Jun 1993 |
|
WO |
|
WO 98/11827 |
|
Mar 1998 |
|
WO |
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WO 98/50387 |
|
Nov 1998 |
|
WO |
|
Other References
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Svetlana V.; Lewis, Karina; and Van Lier, Johan E. "Photodynamic
Therapy Of Tumors With Hexadecafluoro Zinc Phthalocyanine
Formulated In Peg-Coated Poly (Lactic Acid) Nanoparticles." Int. J.
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Byers, V.S. and Baldwin, R.W. "Monoclonal Antibody Conjugates with
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vaccine formulation: the surface attachment of hydrophilic species
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in Drug Targeting," Journal of Molecular Recognition, vol. 9. 1996.
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Bioconjugate Techniques. Ch. 15. Academic Press, Inc.: San Diego,
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Human Squamous Cell Carcinoma Cells Using a Monoclonal
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Tumors." Abstract RC63. St. Michael's Hospital and the Princess
Margaret Hospital, University of Toronto, Canada. Undated. 1 pg.
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Torchilin, V. P. "Polymer-coated long-circulating microparticulate
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1998. pp. 1-19. .
Westermann, Patrick; Glanzmann, Thomas; Andrejevic, Snezana;
Braichotte, Daniel R.; Forrer, Martin; Wagnieres, Georges A.;
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|
Primary Examiner: Dvorak; Linda C. M.
Assistant Examiner: Kearney; R.
Attorney, Agent or Firm: Anderson; Ronald M.
Claims
The invention in which an exclusive right is claimed is defined by
the following:
1. A method for destroying abnormal tissue in a patient, at an
internal treatment site comprising the steps of:
(a) providing a conjugate of a microparticle, a photosensitizer, an
antibody and a polymer, the microparticle characterized by being
inert and biocompatible, the photosensitizer characterized by
absorbing light within a defined waveband, the polymer
characterized by having a high molecular weight combined with a
highly flexible main chain, thereby providing steric protection to
the conjugate, and the antibody characterized by being targeted to
an antigen which exists substantially only at the abnormal tissue
in the patient;
(b) administering the conjugate to the patient, said antibody
linking with the abnormal tissue at the treatment site, and said
polymer increasing an in vivo residence time of the conjugate to
allow for an increased uptake of the conjugate by the abnormal
tissue at the treatment site; and
(c) administering light within the defined waveband to the internal
treatment site, said light activating the photosensitizer to
destroy the abnormal tissue.
2. The method of claim 1, wherein the polymer comprises
polyethylene glycol.
3. The method of claim 1, wherein the polymer comprises a
derivative of polyethylene glycol.
4. The method of claim 1, wherein the polymer is water soluble and
hydrophilic.
5. The method of claim 1, wherein the polymer is biocompatible,
exhibiting a low toxicity and a low immunogenicity in a
concentration administered to the patient.
6. The method of claim 1, wherein the polymer must have at least
one attachment site to which the photosensitizer and the antibody
covalently bond.
7. The method of claim 1, wherein the defined waveband includes
wavelengths sufficiently long to readily pass through a dermal
layer of the patient.
8. The method of claim 7, wherein the light is administered
externally to a body of the patient and passes through intervening
tissue to reach the internal treatment site.
9. The method of claim 8, wherein the abnormal tissue is
distributed throughout at least a portion of a body of the
patient.
10. The method of claim 8, wherein the treatment site includes at
least part of a vascular system of the patient, said abnormal
tissue being disposed within said at least part of the vascular
system.
11. The method of claim 1, wherein the abnormal tissue includes at
least one of a disease causing bacteria and a disease causing
virus.
12. The method of claim 1, wherein the step of administering the
light includes the step of inserting a light source that emits
light interstitially within the internal treatment site so that the
light is administered to the internal treatment site.
13. The method of claim 1, wherein the internal treatment site is a
prospective treatment site at which abnormal tissue may possibly
develop, further comprising the steps of:
(a) administering the conjugate to the patient; and
(b) as a prophylaxis, administering the light to the prospective
treatment site.
14. The method of claim 13, wherein the steps of administering the
conjugate and administering the light as a prophylaxis are repeated
at spaced-apart intervals of time to prevent development of the
abnormal tissue at the prospective treatment site from
occurring.
15. The method of claim 1, further comprising the step of
surgically excising a substantial portion of the abnormal tissue,
followed by the steps of administering the conjugate, and
administering the light, to destroy any residual abnormal tissue at
the treatment site.
16. The method of claim 1, further comprising the step of
transplanting bone marrow into the patient, followed by the steps
of administering the polymer protected antibody/photosensitizer
conjugate, and administering the light, to destroy residual
abnormal tissue in the patient.
17. A method for enhancing an efficacy of a light therapy rendered
to destroy abnormal tissue, comprising the steps of:
(a) administering a microparticle, polyethylene glycol (PEG), and a
photosensitizer that is conjugated with an antibody targeted to
bind with antigens present on the abnormal tissue, said
polyethylene glycol serving to extend a viable lifetime of a
resulting conjugate to enable more of said antibody to bind with
the antigens on the abnormal tissue, thereby increasing an uptake
of the conjugate by the abnormal tissue; and
(b) after sufficient time has elapsed following administration of
the conjugate to permit the antibody to bind with the antigens,
administering a light therapy, said light therapy activating the
photosensitizer and more effectively destroying the abnormal tissue
due to the increased uptake of the conjugate by the abnormal
tissue.
18. The method of claim 17, wherein the conjugated photosensitizer
and antibody are coated with said PEG.
19. The method of claim 17, wherein conjugated photosensitizer and
antibody is covalently bonded to said PEG.
20. The method of claim 17, wherein conjugated photosensitizer and
antibody are covalently bonded to different sites on said PEG.
21. A method for preventing abnormal tissue growth in a patient, at
a prospective treatment site at which abnormal tissue may possibly
develop, comprising the steps of:
(a) providing a conjugate comprising a photosensitizer, an
antibody, and a polymer, the photosensitizer characterized by
absorbing light within a defined waveband, the polymer
characterized by having a high molecular weight combined with a
highly flexible main chain, thereby providing steric protection to
the conjugate, and the antibody characterized by being targeted to
an antigen which exists substantially only at abnormal tissue in
the patient;
(b) administering the conjugate to the patient, said antibody
linking with any abnormal tissue at the prospective treatment site,
and said polymer increasing an in vivo residence time of the
conjugate to allow for an increased uptake of the conjugate by any
abnormal tissue at the prospective treatment site; and
(c) as a prophylaxis, administering light within the defined
waveband to the prospective treatment site, said light activating
the photosensitizer to destroy any abnormal tissue being
formed.
22. The method of claim 21, wherein the steps of administering the
conjugate and administering the light as a prophylaxis are repeated
at spaced-apart intervals of time to prevent development of
abnormal tissue at the prospective treatment site from
occurring.
23. A method for destroying abnormal tissue in a patient, at a
prospective treatment site at which a growth of the abnormal tissue
may possible develop, comprising the steps of:
(a) providing a conjugate of a microparticle, a photosensitizer, an
antibody and a polymer, the microparticle characterized by being
inert and biocompatible, the photosensitizer characterized by
absorbing light within a defined waveband, the polymer
characterized by having a high molecular weight combined with a
highly flexible main chain, thereby providing steric protection to
the conjugate, and the antibody characterized by being targeted to
an antigen which exists substantially only at abnormal tissue in
the patient;
(b) administering the conjugate to the patient, said antibody
linking with any abnormal tissue at the prospective treatment site,
and said polymer increasing an in vivo residence time of the
conjugate to allow for an increased uptake of the conjugate by any
abnormal tissue at the prospective treatment site; and
(c) as a prophylaxis, administering light within the defined
waveband to the prospective treatment site, said light activating
the photosensitizer to destroy abnormal tissue.
24. The method of claim 23, wherein the steps of administering the
conjugate and administering the light as a prophylaxis are repeated
at spaced-apart intervals of time to prevent development of
abnormal tissue at the prospective treatment site from
occurring.
25. A method for destroying abnormal tissue in a patient, at an
internal treatment site, comprising the steps of:
(a) providing a polymer protected conjugate comprising a polymer
suitable for increasing an in vivo residence time of said
conjugate, a photosensitizer bound to said polymer, and a targeting
antibody bound to said photosensitizer but not to said polymer, the
photosensitizer being characterized by absorbing light within a
defined waveband, the polymer being characterized by having a high
molecular weight combined with a flexible main chain, thereby
providing steric protection to the conjugate, and the antibody
being characterized by being targeted to an antigen that exists
substantially only at the abnormal tissue in the patient;
(b) administering the polymer protected conjugate to the patient,
said antibody linking with the abnormal tissue at the treatment
site, and said polymer increasing the in vivo residence time of the
conjugate to provide sufficient time for uptake of the conjugate by
the abnormal tissue at the treatment site; and
(c) administering light within the defined waveband to the internal
treatment site, said light activating the photosensitizer to
destroy the abnormal tissue.
Description
FIELD OF THE INVENTION
The present invention is generally related to the use of light
therapy to destroy abnormal tissue that has absorbed a
photosensitizer, and more specifically, to the use of a
photosensitizer that is targeted to bind with the abnormal tissue,
but not normal tissue, so that the light administered during the
therapy has a minimal adverse effect on surrounding normal tissue,
which is generally free of the photosensitizer.
BACKGROUND OF THE INVENTION
Abnormal tissue in the body is known to selectively absorb certain
photosensitizer dyes that have been administered to a patient to a
much greater extent than normal tissue surrounding a treatment
site. For example, tumors of the pancreas and colon may absorb two
to three times the volume of these dyes, compared to normal tissue.
The cancerous or abnormal tissue that has absorbed the
photosensitizer dye can then be destroyed by administering light of
an appropriate wavelength or waveband corresponding to an absorbing
wavelength or waveband of the photosensitizer dye. This procedure,
which is known as photodynamic therapy (PDT), has been clinically
used to treat metastatic breast cancer, bladder cancer, lung
carcinomas, esophageal cancer, basal cell carcinoma, malignant
melanoma, ocular tumors, head and neck cancers, and other types of
malignant tumors. Because PDT may selectively destroy abnormal
tissue that has absorbed more of the dye than normal tissue, it can
successfully be used to kill the malignant tissue of a tumor with
less effect on surrounding benign tissue than alternative treatment
procedures, such as traditional chemotherapy or radiation
therapy.
However, even those photosensitizers that are much more selectively
absorbed by abnormal tissue will still be absorbed to some lesser
extent by the normal tissue of a patient's body. If the light
therapy administered is limited primarily to the abnormal tissue at
the treatment site so that very little light is applied to the
adjacent normal tissue, which has absorbed the photosensitizer to a
lesser extent, the effect of the light therapy on such normal
tissue will be minimal. To enable the selective application of
light therapy to an internal treatment site with minimal exposure
of surrounding normal tissue, it is typically necessary to either
surgically expose the internal treatment site, or insert an
appropriate light source probe into the patient's body and advance
it to the treatment site, for example, using conventional
endoscopic procedures, or insert a light source probe
interstitially into a tumor.
More recently, techniques have been developed for administering
light therapy to an internal treatment site from an externally
disposed light source. These techniques take advantage of the fact
that light having a relatively long wavelength will readily
penetrate dermal tissue to activate photosensitizers absorbed by
abnormal tissue at an internal treatment site. The disadvantage of
this approach is that normal tissue lying between the light source
and the internal treatment site is also is irradiated by the light
as it passes through the overlying tissue to the internal treatment
site. Skin and other normal tissue in the propagation path of the
light administered externally to render PDT to an internal
treatment site will thus be adversely affected by the therapy. The
effects of the light therapy on normal tissue that has absorbed the
photosensitizer may range from mild reddening of the skin to severe
damage to the normal dermal tissue. Clearly, it would be desirable
to minimize damage to the normal tissue by substantially reducing
the extent to which the normal skin and tissue absorb the
photosensitizer.
One approach developed to address the preceding problems is to bind
antibodies to a photosensitizer that are targeted to the abnormal
cells at a treatment site. When a photosensitizer conjugated with
an antibody is administered to a patient, the antibodies will tend
to bind the photosensitizer to the abnormal tissue, but not to
normal tissue, thereby improving the specificity of the PDT and
avoiding harm to the normal tissue. However, it has been shown that
targeted photosensitizers that are conjugated with an antibody can
have a relatively low uptake by abnormal tissue in a tumor. In some
cases, as little as 0.1% of an injected dose of photosensitizer is
actually absorbed by the abnormal cells in a tumor. The low tumor
uptake of antibody targeted photosensitizers (or other drugs) is
due in part to the rapid plasma clearance by the
reticuloendothelial system and poor penetration of the targeted
conjugate across vascular endothelium. In effect, the targeted
photosensitizer is cleared too rapidly from the plasma in the
patient's body to have an opportunity to bind the antibody with the
abnormal tissue at the levels desired.
More generally, too rapid clearance of conventional
photosensitizers (i.e., a non-targeted photosensitizer) from plasma
has also been recognized as problem. One solution that has been
explored is the use of a synthetic drug carrier such as
polyethylene glycol (PEG). As previously reported by others, PEG
coated microparticulates containing a photosensitizer (zinc
phthalocyanine) have been tested in vivo. In addition, V.P.
Torchilin has published an article entitled, "Polymer-coated
Long-Circulating Microparticulate Pharmaceuticals," in Journal
Microencapsulation, vol. 15, no. 1, (1998) pp. 1-19, in which he
discusses the protective effect of certain polymers, including PEG,
on nanoparticulate drug carriers, including micelles, for extending
the circulation time of the encapsulates in solution. PEG is well
known as a sterically protecting polymer and drug carrier. Useful
biological properties of PEG include its water solubility, low
immunogenicity, and extended life while circulating in mammalian
organisms. A PEG dextran conjugate has been used as a combined
stabilizer and surface modifier to produce resorbable
poly(DL-lactide-co-glycolide) (PLG) microparticles by an
emulsification/solvent technique as described by A.G.A. Coombes et
al. in "Biodegradable Polymeric Microparticles for Drug Delivery
and Vaccine Formulation: the Surface Attachment of Hydrophilic
Species Using the Concept of Poly(ethylene glycol) Anchoring
Segments," in Biomaterials 1997, vol. 18, No. 17, page 1153.
However, it appears that protectively polymerized drugs have not
been conjugated with antibodies that can target the drugs to
abnormal tissue. Clearly, the combination of a polymer such as PEG
to protect a photosensitizer that is conjugated with an antibody
could solve both the too rapid clearing of conventional targeted
photosensitizer conjugates from the plasma and ensure that the
photosensitizer binds only to the abnormal tissue, to substantially
eliminate any damage to the normal tissue by the light therapy.
Such a combination has not been disclosed or suggested by the prior
art.
SUMMARY OF THE INVENTION
In accord with the present invention, a method for destroying
abnormal tissue within a patient's body is defined. The method
includes the step of providing a photosensitizer that is
characterized by absorbing light within a defined waveband. The
photosensitizer is sterically protected by a polymer and is
conjugated with an antibody that is targeted at the abnormal
tissue, producing a polymer protected antibody/photosensitizer
conjugate. When the polymer protected antibody/photosensitizer
conjugate is administered to the patient, the antibody portion of
the conjugate preferentially links with the abnormal tissue at the
treatment site, while the polymer increases an in vivo residence
time of the antibody/photosensitizer conjugate within the patient's
body. Consequently, there is an increased uptake of the
antibody/photosensitizer conjugate by the abnormal tissue at the
treatment site. Light within the defined waveband is administered
to the internal treatment site, thereby activating the
photosensitizer to destroy the abnormal tissue.
The polymer in the above-described method is preferably
polyethylene glycol or a derivative of polyethylene glycol and is
water soluble, hydrophilic, and biocompatible. In addition, the
polymer exhibits a low toxicity and a low immunogenicity, is not
biodegradable, and does not form any toxic metabolites. Other
desired characteristics of the polymer include a high enough
molecular weight, combined with a highly flexible main chain to
provide for long in vivo residence times in a human body. The
polymer should have at least one attachment site to which the
photosensitizer and antibody may be covalently bonded.
The wavelengths of the light used when administering the light
therapy from an external source are sufficiently long to readily
pass through a dermal layer and through intervening tissue to reach
the internal treatment site. Instead of being administered
externally, the light may be administered internally using a light
source disposed interstitially so that the light is administered to
the treatment site within a patient's body.
The treatment site may be localized, such as at a tumor, or it may
be disseminated throughout at least a portion of the patient's
body, and the abnormal tissue may be distributed throughout the
treatment site. The treatment site may include at least part of a
vascular system of the patient in which the abnormal tissue is
disposed. Furthermore, the abnormal tissue may be a tumor,
non-localized malignant cells, or may be a disease causing bacteria
or a disease causing virus.
The method described above may serve as a prophylaxis by
administering the polymer protected antibody/photosensitize
conjugate and administering light to a prospective treatment site
at which abnormal tissue may possibly develop. This prophylactic
treatment may be repeated at intervals to prevent development of
the abnormal tissue within the patient.
It is also contemplated that the method described above may be used
following the surgical removal of a substantial portion of the
abnormal tissue, to destroy any residual abnormal tissue at the
treatment site, or following the transplanting of bone marrow into
a patient, to destroy residual abnormal tissue in the patient's
body.
Another aspect of the present invention is directed to a method to
improve a specificity with which a photosensitizer is taken up by
abnormal cells within a patient. In this further aspect of the
invention, a microparticle, a photosensitizer, an antibody that is
targeted at antigens on the abnormal cells, and a polymer are
provided. The antibody and the photosensitizer are conjugated to
the microparticle, and the microparticle is coated with a polymer
that prolongs an in vivo residence time for the microparticle based
antibody/photosensitizer conjugate. When the polymer coated
microparticle based antibody/photosensitizer conjugate is
administered to a patient, the antibody on the conjugate links with
the abnormal cells. The linking action of the antibody and ability
of the polymer coating to increase the in vivo residence time
results in a higher uptake of the polymer coated microparticle
based antibody/photosensitizer conjugate by the abnormal cells than
would be possible using a microparticle based
antibody/photosensitizer conjugate that is not coated with the
polymer.
The microparticle may comprise a micelle. Preferably, the polymer
is PEG.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
The foregoing aspects and many of the attendant advantages of this
invention will become more readily appreciated as the same becomes
better understood by reference to the following detailed
description, when taken in conjunction with the accompanying
drawings, wherein:
FIG. 1 schematically illustrates a first form of a polymer
protected antibody/photosensitizer conjugate microparticle;
FIG. 2 is a schematic view showing the polymer protected
antibody/photosensitizer conjugate of FIG. 1 bound to a target
malignant cell organelle by the antibody;
FIG. 3A schematically illustrates a second form of a polymer
protected antibody/photosensitizer conjugate in which a
photosensitizing agent and an antibody are bonded to a polymer at
separate attachment sites; FIG. 3B schematically illustrates a
third form of a polymer protected antibody/photosensitizer
conjugate in which a photosensitizing agent and an antibody are
bonded to a polymer at the same attachment site;
FIG. 4 is a schematic view of the third form of a polymer protected
antibody/photosensitizer conjugate bound to a target malignant cell
organelle by the antibody;
FIG. 5 is a schematic cross-sectional view of a portion of a
patient's body in which a blood vessel is disposed, showing the
polymer protected antibody/photosensitizer conjugates being
injected into the patient's bloodstream with a syringe;
FIG. 6 is a schematic cross-sectional view of a portion of a
patient's body containing a tumor, showing an external long
wavelength light source being used to activate the photosensitizers
in the polymer protected antibody/photosensitizer conjugates that
are linked to the abnormal tissue in the tumor; and
FIG. 7 is a schematic cross-sectional view of a portion of a
patient's body containing a tumor, showing an internal light source
being used to activate the photosensitizers in the polymer
protected antibody/photosensitizer conjugates that are linked to
the abnormal tissue in the tumor.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Polymer Protected Antibody/Photosensitizer Conjugates
Referring to FIG. 1, a polymer protected antibody/photosensitizer
conjugate 10a in accordance with the present invention is
schematically illustrated. Polymer protected
antibody/photosensitizer conjugate 10a includes a microparticle
core 12 of the type normally used as a drug carrier. It is
contemplated that the microparticle may be a micelle or a carrier,
such as a latex sphere. Other inert, biocompatible microparticles
may be used for the core or carrier. The choice of the particular
microparticle will be determined by a number of factors, including
the chemical compatibility of the microparticle with the antibody,
the photosensitizer, and the polymer.
Attached to the surface of microparticle core 12 are a plurality of
antibody linking sites 20, which are specifically targeted to link
with antigens on abnormal tissue, or malignant cell organelles, or
disease causing organisms within a patient's body. Note that as
used herein and in the claims that follow, unless otherwise evident
from the context, the term "abnormal tissue" is intended to
encompass malignant cell organelles and disease causing organisms.
Also attached to the surface of microparticle core 12 are a
plurality of photosensitizers 18 of the type suitable for use in
administering PDT.
Microparticle core 12 is coated with a polymer 16. Polymer 16
increases the in vivo residence time of the
antibody/photosensitizer conjugates within the patient's body,
e.g., within the plasma, allowing a lower dose of the
photosensitizer conjugate to be used, while simultaneously
increasing the uptake of the antibody/photosensitizer conjugate by
the abnormal tissue. Polymer 16 is preferably polyethylene glycol
(PEG) or PEG based, having a moderately high molecular weight,
e.g., on the order of 20,000. Other polymers that exhibit similar
properties may also be used to extend the residence time of the
photosensitizer targeted conjugate within the patient's body. The
polymer selected for this purpose must be: water soluble,
hydrophilic, biocompatible, must exhibit a low toxicity, and must
have a low immunogenicity. In addition, the polymer must not be
biodegradable or form any toxic metabolites, must have a
sufficiently high molecular weight, coupled with a highly flexible
main chain, to provide for relatively long in vivo residence times
in a human body, e.g., for more than several hours, and must be
chemically compatible with the photosensitizer and antibody used
for the conjugate.
An understanding of how the polymer coating results in longer in
vivo residence times is helpful in designing a microparticle based
polymer protected antibody/photosensitizer conjugate in accord with
the present invention. Polymer 16 comprises a long, highly flexible
main chain and has a moderately high molecular weight (which means
that the main chain is longer in length than most molecules). The
flexible main chain is in constant motion, creating a "cloud,"
which protects the surface of the microparticle and dramatically
increases in vivo residence times. However, this same "cloud" may
also tend to inhibit antibody link sites 20 from successfully
binding with corresponding antigens on the target abnormal tissue.
The prior art teaches that relatively minor amounts (1-2 mol%) of a
polymer such as PEG provide sufficient protection to increase in
vivo residence time, while higher concentrations tend to inhibit
antibody linking. It is therefore anticipated that the optimal
concentration of polymer used in producing a conjugate will need to
be empirically determined for each different microparticle based
polymer protected antibody/photosensitizer conjugate species.
FIG. 2 illustrates how targeted polymer protected
antibody/photosensitizer conjugate 10a is used for destroying a
malignant cell organelle 22. In this Figure, targeted polymer
protected antibody/photosensitizer conjugate 10a is shown with one
of the antibody link sites 20 linked to an antigen 24 that is
associated with the malignant cell organelle. Because normal cells
do not have any antigen to which antibody link sites 20 will bind,
targeted polymer protected antibody/photosensitizer conjugates 10a
do not become bound to normal cells. After providing sufficient
time for the targeted polymer protected antibody/photosensitizer
conjugates to bind to the malignant cell organelles or other types
of abnormal tissue within a patient's body, a light 154 having a
waveband corresponding to a characteristic light absorption
waveband of the photosensitizer is applied using one of the
techniques disclosed hereinbelow. This light activates a
photosensitizer 18, causing it to form new chemical species, such
as free oxygen radicals, which attack the target malignant cells or
other abnormal tissue.
FIGS. 3A and 3B illustrate forms of polymer protected
antibody/photosensitizer conjugates, which do not incorporate a
microparticle core. In these embodiments, the
antibody/photosensitizer conjugate is covalently bonded to the
polymer rather than being attached to a microparticle. FIG. 3A
illustrates polymer protected antibody/photosensitizer conjugate
10b in which photosensitizer 18 is covalently bonded to one
attachment site of polymer 26a, while the antibody which includes
antibody link site 20 is covalently bonded to a different
attachment site of polymer 26a. Polymer 26a is preferably PEG,
which has one attachment site at each end of the polymer chain.
FIG. 3B illustrates polymer protected antibody/photosensitizer
conjugate 10c in which photosensitizer 18 is covalently bonded to
one attachment site of polymer 26b, while the antibody which
includes antibody link site 20 is covalently bonded to
photosensitizer 18. Polymer 26b is preferably methyl-PEG, a PEG
derivative which has only a single attachment site at one end of
the polymer chain; the other attachment site having been replaced
with a methyl group.
For the two forms of the polymer protected antibody/photosensitizer
conjugate respectively illustrated in FIGS. 3A and 3B, it is
important that antibody link site 20 be positioned in such a manner
as to allow it easy access to corresponding antigen 24 on the
targeted malignant cell organelle or other abnormal tissue, as
illustrated in FIGS. 2 and 4. The relative positions of polymers
26a and 26b, antibody link site 20, and photosensitizer 18, as
shown in FIGS. 3A and 3B, are not the only possible configurations.
Actual positional configurations of the conjugates will be a
function of the polymer chosen and the attachment sites available.
Some polymers have a plurality of attachments sites available, thus
a plurality of antibody link sites 20 and/or photosensitizers 18
may be covalently bonded to a single polymer molecule. The
selection of polymer 26a or 26b will be based on the chemical
compatibility of the polymer, antibody 20, and photosensitizer 18.
Those skilled in the art will readily understand that appropriate
chemical manipulations and processes will be required to form the
desired polymer protected antibody/photosensitizer conjugate, and
the ease or difficulty of such manipulations and processes will
factor decisively in the ultimate configuration of the polymer
protected antibody/photosensitizer conjugate employed.
FIG. 4 illustrates how targeted polymer protected
antibody/photosensitizer conjugate 10c is used for destroying a
malignant cell organelle 22. In a manner similar that of FIG. 2,
targeted polymer protected antibody/photosensitizer conjugate 10c
is shown with antibody link site 20 bound to an antigen 24. After
providing sufficient time for targeted conjugates 10c to bind to
the targeted abnormal tissue, light 154 of an appropriate waveband,
i.e., corresponding to the absorption waveband of the
photosensitizer, is applied using one of the techniques disclosed
hereinbelow. The light activates photosensitizer 18, destroying the
abnormal tissue.
Injection of Targeted Polymer Protected Antibody/Photosensitizer
Conjugates
It is generally preferable to introduce the polymer protected
antibody/photosensitizer conjugates as close as possible to a
treatment site, such as by introducing the polymer protected
antibody/photosensitizer conjugate directly into a tumor. At times,
the location of a tumor or other treatment site is such that it is
not feasible to localize the administration of the polymer
protected antibody/photosensitizer conjugate. Furthermore, the
targeted abnormal tissue may not be localized, but instead, may be
viruses, microorganisms or metastasized cancer cells, which are
more broadly distributed throughout a patient's body. It is
therefore contemplated that polymer protected
antibody/photosensitizer conjugates 10a, 10b, and 10c may be
injected into the patient's bloodstream to allow the patient's own
circulatory system to deliver the polymer protected
antibody/photosensitizer conjugates to the targeted abnormal
tissue. As illustrated in FIG. 5, a syringe 58 can be used to
inject a fluid containing the targeted polymer protected
antibody/photosensitizer conjugates in suspension through a dermal
layer 70 and into a bloodstream 72. A needle 60 passes through
dermal layer 70 and through a wall 76 of bloodstream 72; fluid
containing the targeted polymer protected antibody/photosensitizer
conjugates is injected through needle 60 into blood 74. The blood
flow in the vessel carries the targeted polymer protected
antibody/photosensitizer conjugates downstream, to one or more
locations where the targeted abnormal tissue is disposed. It is
important to note that antibody link sites 20 will seek out and
bind only to the selected targeted abnormal tissue, which
incorporates antigen 24, as shown in FIGS. 2 and 4. Since the
photosensitizer is not linked to normal tissue, injury to normal
tissue is minimized during administration of the light,
particularly, if the light is administered from an external source
and must pass through normal tissue to reach the abnormal tissue
that has been targeted.
Activation of the Photosensitizer
The photosensitizer in the polymer protected
antibody/photosensitizer conjugate destroys abnormal tissue to
which it is bound when light of the proper waveband is
administered. While the mechanism by which PDT destroys cells is
not fully understood, it is believed to produce free oxygen
radicals that are toxic to the abnormal tissue.
In FIG. 6, a tumor 140 has been infused with polymer protected
antibody/photosensitizer conjugates 64. These conjugates may be of
the forms illustrated in FIGS. 1, 3A, or 3B (i.e., conjugates 10a,
10b, and 10c, respectively). The polymer protected
antibody/photosensitizer conjugates can be infused either within a
biocompatible fluid, such as a physiological saline solution, or
can be applied topically to the exterior surface of tumor 140.
Tumor 140 lies within the patient's body, adjacent a dermal layer
144. Outside the patient's body, a power supply 150 is coupled
through a lead 148 to an external light array 146. Array 146
comprises a plurality of light sources 152 such as LEDs. When
energized by power supply 150, light sources 152 emit light 154 of
the desired wavelength that passes freely through the dermal layer
and into tumor 140, activating photosensitizer 18 that is included
within polymer protected antibody/photosensitizer conjugates 64, so
that photosensitizer 18 produces substances that attack tumor
140.
FIG. 7 illustrates yet another technique for exposing polymer
protected antibody/photosensitizer conjugates 64 to light 154 of
the waveband corresponding to the light absorption waveband of the
photosensitizer. In this approach, a probe 160 is inserted
interstitially within tumor 140. Probe 160 includes a linear array
162 of LEDs (or other appropriate light sources) that are energized
through a lead 164. Lead 164 is coupled to a remote internal (or
external) power supply (not shown). If disposed internally, the
power supply can be energized using an external power source that
is electromagnetically coupled to the internal power supply. A
detailed description of apparatus suitable for providing such
electromagnetic coupling is provided in U.S. Pat. No. 5,715,837,
which is assigned to the same assignee as the present invention,
the disclosure and drawings of which are hereby specifically
incorporated herein by reference.
As noted above, the targeted abnormal tissue may not be a localized
tumor, but instead, may comprise metastasized cancer cells, disease
causing viruses, disease causing bacteria or other undesirable
microorganisms that are distributed throughout at least a portion
of the patient's body. In this instance, the light employed for
administering the light therapy preferably has a relatively long
wavelength, e.g., longer than 800 nm, to enable the light to pass
through several cm. of tissue. Generally, the longer the wavelength
of the light, the greater its ability to penetrate tissue in the
body of the patient. Of course, the light adsorption waveband of
the photosensitizer must be matched to the wavelength or waveband
of the light that is administered to activate the photosensitizer.
It is contemplated that by passing a long wavelength light source
over the external surfaces of a patient's body, the majority of the
polymer protected antibody/photosensitizer conjugates attached to
targeted abnormal tissue may be activated, thus destroying the
abnormal tissue, even though widely disseminated within the
patient's body.
It is also contemplated that polymer protected
antibody/photosensitizer conjugates can be employed
prophylactically to prevent the development of abnormal tissue at a
prospective treatment site. For example, it is now possible to
identify women with susceptibility to certain types of breast
cancer based upon genetic testing. The probabilities of developing
breast cancer in a women who has tested positive for the
susceptible genes is so significant that some women choose to
undergo prophylactic radical mastectomy to minimize the risk of
later developing breast cancer. Instead, the present invention can
provide an alternative prophylaxis, by providing for repetitive
administration of a polymer protected antibody/photosensitizer
conjugate targeted at the type of cancerous tumor cells that might
develop, followed by administration of light therapy using light
having a waveband corresponding to the light adsorption waveband of
the photosensitizer. By periodically repeating such prophylactic
therapy, development of cancerous tumor cells in the woman's breast
can likely be prevented, but without the trauma involved in
undergoing a radical mastectomy.
Another application of the present invention is for destroying any
residual abnormal tissue that may remain at a tumor resection site,
following surgical removal of the tumor. A common problem following
such surgery is the regrowth of the tumor. After administering a
polymer protected antibody/photosensitizer conjugate targeted at
antibodies of the tumor that was removed, light therapy can be
administered to destroy the residual tumor cells that have linked
with the conjugate, thereby preventing the regrowth of the tumor.
Such post-surgical treatment might be rendered, for example,
following a mastectomy or brain tumor removal.
Yet another application of the present invention is in the
treatment of leukemia or other diseases requiring bone marrow
transplant. A polymer protected antibody/photosensitizer conjugate
targeted at malignant antigens in the bone marrow can be
administered followed by administration of light therapy using
light of the appropriate waveband, as noted above. This treatment
should be effective both pre- and post-bone marrow transplant to
destroy much of the abnormal tissue causing the leukemia, and may
be employed, in addition to more conventional radiation and
chemotherapy treatments. It is also contemplated that the present
invention may be used for destroying abnormal tissue in bone
marrow, thereby avoiding the need for a bone marrow transplant. The
polymer protected antibody/photosensitizer conjugate may be
activated with light administered either from an interstitial
source or an external source, i.e., transcutaneously or from within
the patient's body.
While empirical evidence such as may be developed by clinical
trials of the present invention have not yet been provided, it is
believed by some authorities that antibodies like those used in the
polymer protected antibody/photosensitizer conjugate may activate
the body's own immune system. Furthermore, photodynamic activation
of a photosensitizer has been demonstrated to also cause an immune
response. It is expected that the present invention will produce a
synergistic effect in enhancing the efficacy of PDT that is far
greater than either of these processes alone. The use of a polymer
such as PEG to protect a targeted photosensitizer is also expected
to provide a much greater improvement in the efficacy of the
conjugate than might be expected relative to the use of a PEG
photosensitizer conjugate alone or a targeted photosensitizer
alone.
Although the present invention has been described in connection
with the preferred forms of practicing it and modifications
thereto, those of ordinary skill in the art will understand that
many other modifications can be made within the scope of the claims
that follow. Accordingly, it is not intended that the scope of the
invention in any way be limited by the above description, but
instead be determined entirely by reference to the claims that
follow.
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